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Palbociclib plus endocrine therapy versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (Young-PEARL): overall survival analysis of a randomised, open-label, phase 2 study
No full textBackground The phase 2 randomised Young-PEARL study demonstrated that palbociclib plus exemestane with ovarian function suppression significantly prolonged progression-free survival compared with capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Here, we report results of the protocol-specified secondary endpoint of overall survival. Methods Young-PEARL was a multicentre, randomised, open-label, phase 2 study conducted at 14 institutions in South Korea. Premenopausal women aged 19 years or older with histologically confirmed hormone receptor-positive, HER2-negative metastatic breast cancer that recurred or progressed during or after previous tamoxifen treatment, who were aromatase inhibitor naive, and had an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. One previous line of chemotherapy was permitted in the metastatic setting. Eligible patients were randomly assigned (1:1), using block randomisation (block size of two) stratified by previous chemotherapy for metastatic breast cancer and presence of visceral metastasis, to receive either palbociclib (orally, 125 mg per day on a 3-weeks-on, 1-week off schedule) plus exemestane (orally 25 mg daily) with leuprorelin (subcutaneously 3<middle dot>75 mg on day 1 of each 28-day cycle) or capecitabine (orally, 1250 mg/m(2) twice a day on a 2-weeks-on, 1-week-off schedule) until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival. Overall survival was a secondary endpoint. All analyses were done in the modified intention-to-treat population (ie, included all patients randomly assigned to treatment who had at least one post-baseline CT scan and excluded those who did not receive study medication and who had any major violation of the eligible criteria). Safety was assessed in all patients who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02592746, and is now complete. Findings Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled. 184 patients were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92), of whom 174 were included in the modified intention-to-treat population (n=90 in the palbociclib plus endocrine therapy group and n=84 in the capecitabine group). All patients were female and ethnicity data were not collected. As of data cutoff (Feb 29, 2024), median follow-up was 54<middle dot>0 months (IQR 34<middle dot>1-74<middle dot>4). Median progression-free survival was 19<middle dot>5 months (90% CI 14<middle dot>3-22<middle dot>2) for palbociclib plus endocrine therapy and 14<middle dot>0 months (11<middle dot>7-18<middle dot>7) for capecitabine (hazard ratio 0<middle dot>74 [90% CI 0<middle dot>57-0<middle dot>98]; one-sided log-rank p=0<middle dot>036). 52 (58%) of 90 patients in the palbociclib plus endocrine therapy group and 48 (57%) of 84 in the capecitabine group died, with a median overall survival of 54<middle dot>8 months (95% CI 48<middle dot>9-77<middle dot>1) in the palbociclib plus endocrine therapy group versus 57<middle dot>8 months (46<middle dot>3-89<middle dot>2) in the capecitabine group (hazard ratio 1<middle dot>02 [95% CI 0<middle dot>69-1<middle dot>51]; p=0<middle dot>92). The most common grade 3 or worse adverse event was neutropenia (59 [64%] of 92 in the palbociclib plus endocrine therapy group vs 15 [18%] of 85 in the capecitabine group) . No treatment-related deaths occurred. Interpretation With extended follow-up, palbociclib plus exemestane with ovarian function suppression continued to show a significant benefit in progression-free survival compared with capecitabine in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had been previously treated with tamoxifen; however, no improvement in overall survival was seen. Given the progression-free survival benefit, the upfront use of palbociclib plus endocrine therapy is the preferred option for premenopausal women, although a capecitabine-first strategy might be an alternative treatment strategy for maintaining overall survival in resource-limited settings. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.N
Cellular dsRNA interactome captured by K1 antibody reveals the regulatory map of exogenous RNA sensing
No full textRNA-binding proteins (RBPs) provide a critical post-transcriptional regulatory layer in determining RNA fate. Currently, UV crosslinking followed by oligo-dT pull-down is the gold standard in identifying the RBP repertoire of poly-adenylated RNAs, but such method is ineffective in capturing RBPs that recognize double-stranded RNAs (dsRNAs). Here, we utilize anti-dsRNA K1 antibody immunoprecipitation followed by quantitative mass spectrometry to comprehensively identify RBPs bound to cellular dsRNAs without external stimulus. Notably, our dsRNA interactome contains proteins involved in sensing N6-methyladenosine RNAs and stress granule components. We further perform targeted CRISPR-Cas9 knockout functional screening and discover proteins that can regulate the interferon (IFN) response during exogenous RNA sensing. Interestingly, most dsRBPs promote IFN-beta secretion in response to dsRNA stimulation and act as antiviral factors during HCoV-OC43 infection. Our dsRNA interactome capture provides an unbiased and comprehensive characterization of putative dsRBPs and will facilitate our understanding of dsRNA sensing in physiological and pathological contexts.N
A long-term reconstruction of a global photosynthesis proxy over 1982-2023
No full textSatellite-observed solar-induced chlorophyll fluorescence (SIF) is a powerful proxy for the photosynthetic characteristics of terrestrial ecosystems. Direct SIF observations are primarily limited to the recent decade, impeding their application in detecting long-term dynamics of ecosystem function. In this study, we leverage two surface reflectance bands available both from Advanced Very High-Resolution Radiometer (AVHRR, 1982-2023) and MODerate-resolution Imaging Spectroradiometer (MODIS, 2001-2023). Importantly, we calibrate and orbit-correct the AVHRR bands against their MODIS counterparts during their overlapping period. Using the long-term bias-corrected reflectance data from AVHRR and MODIS, a neural network is trained to produce a Long-term Continuous SIF-informed Photosynthesis Proxy (LCSPP) by emulating Orbiting Carbon Observatory-2 SIF, mapping it globally over the 1982-2023 period. Compared with previous SIF-informed photosynthesis proxies, LCSPP has similar skill but can be advantageously extended to the AVHRR period. Further comparison with three widely used vegetation indices (NDVI, kNDVI, NIRv) shows a higher or comparable correlation of LCSPP with satellite SIF and site-level GPP estimates across vegetation types, ensuring a greater capacity for representing long-term photosynthetic activity.Y
Dietary patterns and all-cause and cardiovascular disease, and cancer mortality in Korean adults
No full textBackgroundExamining dietary patterns in relation to mortality offers a more comprehensive view of food and nutrient intake. However, to our knowledge, the association of the Korean population's dietary patterns with mortality remains scarce and unclear. We aim to investigate the association between dietary patterns and all-cause, cardiovascular disease (CVD), and cancer mortality in the Korean population.MethodsThis prospective cohort study included 18,019 men and 26,604 women aged >= 19 years who participated in the Korea National Health and Nutrition Examination Surveys 2007-2015. Dietary data were collected from a 24-hour dietary recall. Mortality from all causes, CVD, and cancer were ascertained from linkage to Statistics Korea. We identified dietary patterns through factor analysis. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of the all-cause, CVD, and cancer mortality according to diet pattern scores.ResultsDuring a mean follow-up of 8.19 person-years, 2,622 deaths were identified, with 595 due to CVD and 827 due to cancer. Factor analysis based on 22 food groups, three dietary patterns were obtained: (1) "animal food and condiment pattern," (2) "seafood and vegetable pattern," and (3) "dairy products and processed meat pattern." After multivariable adjustment, the "seafood and vegetable pattern" score was associated with a lower risk of all-cause and CVD mortality. HRs (95% CIs) for all-cause mortality for the second to the highest quintile of "seafood and vegetable pattern", compared with the first quintile were 0.86 (0.75-0.99), 0.75 (0.65-0.87), 0.81 (0.69-0.94), and 0.87 (0.73-1.05), respectively (P for trend = 0.191). For CVD mortality, the HRs were 0.82 (0.62-1.07), 0.80 (0.58-1.08), 0.70 (0.50-0.99), and 0.63 (0.42-0.96), respectively (P for trend = 0.027). No statistically significant associations were found in "animal food and condiment pattern" or "dairy products and processed meat pattern" for all-cause, CVD, and cancer mortality.ConclusionsWe observed that the "seafood and vegetable" dietary pattern decreased the risk of all-cause and CVD mortality in Korean adults.N
Lung-homing nanoliposomes for early intervention in NETosis and inflammation during acute lung injury
No full textAcute lung injury (ALI) is characterized by severe inflammation in lung tissue, excessive immune response and impaired lung function. In hospitalized high-risk patients and cases of secondary infection due to surgical contamination, it can lead to higher mortality rates and require immediate intervention. Currently, clinical treatments are limited in symptomatic therapy as mechanical ventilation and corticosteroids, having insufficient efficacy in mitigating the cause of progression to severe illness. Here we report a pulmonary targeting lung-homing nanoliposome (LHN) designed to attenuate excessive Neutrophil Extracellular Trap formation (NETosis) through sivelestat and DNase-1, coupled with an anti-inflammatory effect mediated by 25-hydroxycholesterol (25-HC), offering a promising intervention for the acute phase of ALI. Through intratracheal delivery, we intend prompt and constant action within the lungs to effectively prevent excessive NETosis. Isolated neutrophils from blood samples of severe ARDS patients demonstrated significant anti-NETosis effects, as well as reduced proinflammatory cytokine secretion. Furthermore, in a murine model of LPS-induced ALI, we confirmed improvements in lung histopathology, and early respiratory function. Also, attenuation of systemic inflammatory response syndrome (SIRS), with notable reductions in NETosis and neutrophil trafficking was investigated. This presents a targeted therapeutic approach that can be applied in early stages of high-risk patients to prevent severe pulmonary disease progression.Y
Different axis approaches for ultrasound-guided centrally inserted central catheterization in children: a systematic review and meta-analysis of randomized controlled trials
No full textBackground: Centrally inserted central catheterization (CICC) is a critical procedure in pediatric care. However, CICC in children poses greater challenges compared to adults due to anatomical and physiological differences, leading to higher complication rates. Ultrasound-guided approaches have been developed to enhance the safety and effectiveness of CICC, but the comparative efficacy of different axis approaches remains unclear. Methods: A systematic review and meta-analysis of randomized controlled trials comparing different axis approaches for ultrasound-guided CICC in children was conducted. Searches were carried out in databases up to June 10, 2024. Six studies were included in the systematic review and three studies were included in the meta-analysis. Primary outcomes included first-attempt success rate, overall success rate, and cannulation time. Secondary outcomes were complications such as hematoma and posterior wall puncture. Results: Data from 547 children were analyzed. The long-axis in-plane approach significantly reduced cannulation time (MD -27.48 s, 95% CI, -33.99 to -20.97) and overall complications OR 0.21, 95% CI, 0.1-0.48) compared to short-axis out-of-plane approach. No significant differences were found in first-attempt or overall success rates between the long-axis and short-axis approaches. Conclusion: The long-axis approach for ultrasound-guided CICC in children offers significant advantages in reducing cannulation time and complications. While dynamic needle tip positioning method may serve as an alternative to in-plane methods, further studies are needed to validate its clinical efficacy. Further research is needed to refine these techniques and explore their application in diverse clinical settings.Y
Highly Stable Porous Nickel-Iron (Oxy)Hydroxide Layer Electrodeposited on Nickel Foam as Anodes for an Anion Exchange Membrane Water Electrolyzer
No full textThe development of high-performance and durable electrodes using anion-exchange membrane water electrolyzers (AEMWEs) is essential for sustainable and highly efficient hydrogen production. In this study, we developed a three-dimensional (3D) porous nickel-iron oxyhydroxide (NiFeOOH) anode for an AEMWE. The porous NiFeOOH layer was directly fabricated onto Ni foam by a one-step electrodeposition process with a pulse current (PC) application without the presence of a nonelectrically conductive ionomer. In addition, the effect of the PC electrodeposited anode on the AEMWE performance and durability was investigated by comparing other anodes (the electrodeposited anode using the direct current (DC) process and the conventional anode using the spraying method). This ionomer-free and porous anode showed a higher performance in reducing the Ohmic resistance than the electrodeposited anode with DC as the sprayed anode. The 3D porous structure enhanced the specific surface area and decreased the mass transport resistance. With those beneficial composition and structure, the AEMWE revealed superior performance, which showed 3.87 A cm-2 at 1.9 V and a small increased overpotential (11.1 mV h-1), compared to other anodes reported to date. 3D p-NiFe@NF was directly employed as a porous transport layer and catalyst layer with superior AEMWE performance and durability.N
Surgical outcomes for Gartland type III supracondylar distal humerus fracture in children: Comparison between flexion and extension types
No full textBackground: Supracondylar distal humeral (SCH) fractures account for 50-70 % of pediatric elbow fractures, which are divided into extension and flexion type based on the injury mechanism. However, there has been no study comparing the surgical outcome between two types of SCH fractures in terms of radiographic and clinical outcomes. This study aimed to compare the surgical outcomes between the flexion and extension types of Gartland type III SCH fractures in children. Materials and methods: This retrospective study included the children who underwent surgery for Gartland type III SCH fractures. Radiographic and clinical outcomes were compared between patients who had extension- and flexion-type fractures. Radiographic outcomes were evaluated by measuring the Baumann angle (BA), carrying angle (CA), and lateral capitellohumeral angle (LCHA). Clinical outcomes were assessed using the Flynn criteria. Univariable and multivariable logistic regression analysis was used to assess the risk factors for angular deformities after surgery. Results: This study included 257 patients (mean age, 6.1 years, 37 flexion-type and 220 extension-type). Pin configuration was significantly different between the two groups (p = 0.001). There were significant differences in radiographic outcomes in terms of BA (p = 0.040) and LCHA (p = 0.001) between the two groups. Flexion-type fractures were a significant risk factor for sagittal deformity, with an odds ratio of 3.225 (p = 0.002). According to the Flynn criteria, a satisfactory outcome (excellent or good) was observed in 158 patients (84.1 %) with the extension type and 25 (67.6 %) with the flexion type, but not statistically significant (p = 0.058). Conclusions: In this study, we found that flexion-type supracondylar fractures had poor radiographic outcomes after surgery compared to extension-type fractures although, there was no significant difference between groups in clinical outcomes. Flexion-type fractures were significantly associated with poor sagittal alignment. Clinicians should focus on alignment during surgery, particularly in flexion-type SCH fractures.N
Longitudinal comparative study on osteogenic capacity using two collagenated xenografts in artificial bone defects in beagles
No full textThis study aimed to evaluate the osteogenic capacity of two types of collagenated xenogenic bone grafts (OCS-B Collagen®, NIBEC, Jincheon, Korea and Bio-Oss® Collagen, Geistlich, Wolhusen, Switzerland) in artificial bone defects in beagle dogs. The bilateral mandibular premolars of 13 male beagles were extracted, followed by the creation of standardized bony defects after 4 weeks. The defects were grafted with or without the two bone grafts and covered by a collagen membrane. Dental implants were placed 24 weeks post grafting. Bone regeneration and osseointegration were evaluated using micro-computed tomography (micro-CT), as well as histological and histomorphometric analyses, while implant stability was measured using resonance frequency analysis (RFA). Micro-CT revealed that both grafts significantly increased bone mineral density (BMD), bone volume (BV), total volume (TV), and BV/TV at 8 and 16 weeks. Twenty-four weeks after implant placement, comparable BMD, BV/TV, and bone-to-implant contact values indicated effective osseointegration. Histological analysis revealed new bone formation and integration between grafts. Histomorphometric analysis demonstrated the preservation of bone height and angle. RFA indicated good implant stability in both groups. The two collagenated xenogenic bone grafts exhibited similar osteogenic potential and osseointegration in an artificial bone defect and implant model. Clinically, both grafting materials may provide comparable outcomes in bone regeneration and implant stability.Y
A Command-Aware Hybrid LDO for Advanced HBM Interfaces with 150μA Quiescent Current and 20pF On-Chip Capacitor Achieving Sub-10mV Voltage Droop in 400ps Settling Time
No full textWith the advent of the generative AI era, high-bandwidth memory (HBM) has emerged as an irreplaceable solution that can provide ultra-high memory bandwidth (BW) of more than 1TB/s to AI processors. To enable such a high BW, HBM3E accommodates 16 channels (CHs) with two pseudo CHs (pCHs) each, and HBM4 increases them to 32 CHs to double the BW. Each pCH receives a dedicated differential write data strobe (WDQS) from the host. Then, the quadrature clocks (WDQS/2INs) at half frequency are passed to the WDQS buffer, which generates the output clocks, SOUT,Xs (X = I, Q, IB, QB), to sample the DQ data in parallel (top left of Fig. 8.5.1). To ensure error-free sampling for all DQs, low jitter is necessary in the SOUT,Xs, but it is difficult to achieve due to the power-supply-induced jitter (PSIJ) issues of the WDQS buffer. A sudden toggle of WDQS/2IN in response to the command signal (ACTCMD) from the host causes a surge in the instantaneous load current (IL) of the WDQS buffer (e.g., edge time (TEDGE) < 100ps) [1] (top right of Fig. 8.5.1). This results in a significant voltage droop in the supply voltage (VDD) and a substantial increase in PSIJ [2]. This problem is particularly severe when the VDD is unstable and noisy due to complex power grids and limited capacitor availability.N